Scn9a encodes NaV1.7, the pore-forming alpha subunit of a tetrodotoxin-sensitive voltage-gated sodium channel of peripheral sensory neurons. The protein has the canonical NaV architecture of four homologous repeats (domains I-IV), each with six transmembrane segments; the S4 segments are the voltage sensors and the four re-entrant S5-S6 pore loops form the sodium-selective pore. On membrane depolarization the channel opens and conducts Na+ down its electrochemical gradient across the plasma membrane, producing the depolarizing upstroke of the action potential. In nociceptors NaV1.7 sets the threshold for action potential initiation, which makes it a principal determinant of pain sensation across mammals. The naked mole-rat protein carries a species-specific charge-changing substitution in the domain IV extracellular P-loop, an acidic EKE triplet in place of the basic KKV triplet found in mouse, rat, rabbit and human. The channel remains a conducting voltage-gated sodium channel, and naked mole-rat nociceptors respond normally to noxious heat and mechanical stimuli, but it is far more potently blocked by extracellular protons than its mouse counterpart. Acidification therefore silences rather than excites naked mole-rat cutaneous nociceptors, and the animal shows no nocifensive response to acid. The same charge inversion at this triplet has arisen repeatedly in other acid-tolerant and hibernating mammals, making it one of the clearest examples of convergent molecular adaptation in mammalian sensory biology.
Definition: Voltage-gated sodium channel activity in which an increase in extracellular proton concentration (a fall in extracellular pH) reduces or blocks sodium conduction through the channel, so that acidification decreases rather than increases the sodium current the channel carries.
Justification: The Gene Ontology currently has no way to state that a channel's own conductance is suppressed by protons, and this is the defining functional property of naked mole-rat NaV1.7 and of the convergent variants found in hibernating and other acid-tolerant mammals. Each candidate existing term fails for a specific reason, checked against QuickGO rather than assumed. GO:0160128 pH-gated monoatomic ion channel activity and its sodium child GO:0160125 are defined as channels that open in response to a change in pH, which is the ASIC/TRPV1 behaviour that naked mole-rat NaV1.7 pointedly does not show; asserting them here would state the opposite of the published mechanism. GO:1905150 regulation of voltage-gated sodium channel activity is a biological process describing a regulator gene product, and its negative-regulation counterpart GO:1905151 is obsolete as of 2025-04-08 with no replacement and no consider term, carrying the comment that it was obsoleted because it represents a molecular function, so the concept was explicitly moved to the molecular function branch without the molecular function term being created. GO:0016248 channel inhibitor activity and GO:0019871 sodium channel inhibitor activity describe the inhibitor, not the inhibited channel, and the inhibitor here is a proton rather than a gene product. GO:1901691 proton binding is discouraged by GO's own comment on GO:0160128, which notes that pH effects on transporters work by protonation of specific residues rather than by proton binding. The biological process terms GO:0010447 response to acidic pH and GO:0071468 cellular response to acidic pH describe a cellular or organismal response and cannot capture a gating property of the channel.
Parent term: voltage-gated sodium channel activity
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001518 voltage-gated sodium channel complex | IEA GO_REF:0000120 | ACCEPT | Summary: NaV1.7 is the pore-forming alpha subunit of a voltage-gated sodium channel, which in vertebrates assembles with auxiliary beta subunits into the channel complex. The naked mole-rat entry retains all four homologous repeats with their pore loops and voltage sensors, so the subunit that defines this complex is complete. Reason: Correct cellular component for a NaV alpha subunit, and the assertion survives the fragment status of this entry: the truncation removes only 22 N-terminal and 87 C-terminal cytoplasmic residues, leaving the four Pfam PF00520 ion-transport domains intact. Structural work on the orthologous human channel resolves the alpha subunit in complex with beta subunits, and the naked mole-rat literature treats this protein as an assembled, conducting channel whose gating is modified rather than as a non-functional subunit. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000004433 · PAINT node cited by the combined-IEA pipeline for this row SUPPORTS TRANSFER The naked mole-rat protein maps to PANTHER PTHR10037:SF221, the NaV1.7 subfamily, so the transfer is within the correct subfamily rather than across paralogous NaV subtypes. Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt Belongs to the sodium channel (TC 1.A.1.10) family. PMID:30765606 Here we report the cryo-electron microscopy structures of the human Nav1.7 file:HETGA/Scn9a/Scn9a-bioinformatics/RESULTS.md The pore-forming and voltage-sensing machinery of the channel is therefore complete in this entry, and the truncation does not undercut molecular-function or cellular-component claims about the channel. |
| GO:0005216 monoatomic ion channel activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR005821 (Ion_trans_dom) is a domain shared by voltage-gated cation channels generally, so InterPro2GO can only assert generic ion channel activity from it. The identity of this protein is known far more precisely. Reason: Not wrong, but uninformatively general. UniProt assigns this entry to PANTHER subfamily PTHR10037:SF221 (the NaV1.7 subfamily) and to the sodium channel family, and the naked mole-rat literature characterizes it specifically as a voltage-gated sodium channel. The specific term GO:0005248 is independently annotated on this protein and is the term this row should collapse to. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR005821 · Ion transport domain SUPPORTS TRANSFER The domain match is real; it is simply shared across voltage-gated cation channels, so the mapped term cannot reach the sodium-specific level. Proposed replacements: voltage-gated sodium channel activity Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt PANTHER; PTHR10037:SF221; SODIUM CHANNEL PROTEIN TYPE 9 SUBUNIT ALPHA; 1. file:HETGA/Scn9a/Scn9a-uniprot.txt Mediates the voltage-dependent sodium ion permeability of |
| GO:0005248 voltage-gated sodium channel activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the core molecular function. The naked mole-rat protein is a functional voltage-gated sodium channel: it was cloned from naked mole-rat sensory tissue and its currents measured, and naked mole-rat nociceptors fire normal action potentials to noxious heat and mechanical stimuli. Its species-specific feature is greatly enhanced block by extracellular protons, which modifies gating without abolishing conduction. Reason: Unusually for a naked mole-rat annotation, this projected term is positively confirmed by naked mole-rat work on this very protein rather than merely transferred from mouse. Smith et al. describe a species-specific variant of this channel that is potently blocked by protons; a channel that can be blocked is a channel that conducts, and the enhanced proton block is a quantitative modification of gating, not a loss of channel activity. Independent reviews restate the same conclusion. My own sequence comparison locates the responsible substitution in the domain IV extracellular P-loop, between the S5 and S6 helices. The physical mechanism of the block is not settled: Harms et al. reproduced the effect by transplanting the motif into human NaV1.7, but modelled the residues as not lining the pore lumen and found that motif charge does not predict proton sensitivity across other NaV subtypes, so the substitution is best described as the sequence correlate of enhanced proton block rather than as a pore-occluding site. Either way it modulates gating rather than removing channel activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000004433 · PAINT node cited by the combined-IEA pipeline for this row SUPPORTS TRANSFER Independently corroborated by naked-mole-rat experimental literature on this protein, so the transfer is not the only support for the term here. Supporting Evidence: PMID:22174253 We describe a species-specific variant of the nociceptor sodium channel Na(V)1.7, which is potently blocked by protons and can account for acid insensitivity in this species. PMID:32206859 The NaV1.7 subunit is particularly important for action potential initiation and the naked mole-rat gene encodes amino acid variations that when mutated into the human protein considerably enhance proton block of NaV1.7 channels at certain pH values that excite nociceptors PMID:24352952 In the naked mole-rat, acid insensitivity has been shown to be conferred by the functional motif of the sodium ion channel NaV1.7. file:HETGA/Scn9a/Scn9a-uniprot.txt Reaction=Na(+)(in) = Na(+)(out) PMID:28939386 The insertion of the negatively charged motif (EKE) of ANMrNav1.7 into human Nav1.7 results in an increased proton-evoked tonic inhibition, but also in a reduced channel function. file:HETGA/Scn9a/Scn9a-deep-research-falcon.md NaV1.7 is not an enzyme. It is an **electrogenic ion channel** whose transported substrate is principally **Na+**. |
| GO:0005261 monoatomic cation channel activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR043203 groups voltage-gated calcium and sodium channels together, so the mapped term can only reach the level of cation channel activity. This protein is a sodium-selective channel. Reason: Correct but too general, and general in a way that obscures the selectivity that matters biologically: the UniProt catalytic-activity statement for this entry is sodium translocation, and the naked mole-rat literature is entirely about sodium currents. GO:0005248 is already annotated and is the term this row should collapse to. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR043203 · Voltage-gated calcium and sodium channel SUPPORTS TRANSFER The signature deliberately spans calcium and sodium channels, so the mapping cannot be more specific than cation; that is a property of the source signature, not an error in it. Proposed replacements: voltage-gated sodium channel activity Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt Reaction=Na(+)(in) = Na(+)(out) PMID:22174253 Acid inhibition of voltage-gated sodium currents is more profound in naked mole-rat nociceptors than in mouse nociceptors, however, which effectively prevents acid-induced action potential initiation. |
| GO:0005886 plasma membrane | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt places this multi-pass membrane protein in the cell membrane, and the mechanism established for it requires that location: a channel can only gate the action potential and be reached by extracellular protons if it sits in the plasma membrane of the sensory neuron. Reason: Supported by the UniProt subcellular-location annotation and by the biology. Naked-mole-rat proton block is measured on nociceptor membrane currents and acts from the extracellular side, so a plasma-membrane location is not merely transferred but required by the published mechanism. I deliberately do not extend this to axon, nerve terminal or node of Ranvier: those localizations are established for the human and mouse orthologs, not in this species. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0039 · Cell membrane SUPPORTS TRANSFER Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt SUBCELLULAR LOCATION: Cell membrane file:HETGA/Scn9a/Scn9a-uniprot.txt Multi-pass membrane protein PMID:31992138 This acid insensitivity is a function of altered ASIC responses compared to mouse19 and a variation in NMR NaV1.7, which renders the channel hypersensitive to proton-mediated block and therefore prevents acid-driven action potential initiation from the skin. file:HETGA/Scn9a/Scn9a-deep-research-falcon.md NaV1.7 performs its transport function in the **plasma membrane**. |
| GO:0006811 monoatomic ion transport | IEA GO_REF:0000002 | MODIFY | Summary: Generic ion transport, mapped from the shared ion-transport domain. The specific process this protein carries out, sodium ion transmembrane transport, is independently annotated on the same protein. Reason: A strict ancestor of GO:0035725, which is already present on this gene product and which the evidence supports directly. Keeping the generic parent adds no information about what this channel does. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: sodium ion transmembrane transport Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt Reaction=Na(+)(in) = Na(+)(out) |
| GO:0006814 sodium ion transport | IEA GO_REF:0000002 | MODIFY | Summary: Sodium transport is correct, but for a channel in the plasma membrane the informative term is the transmembrane-transport child, which is already annotated from the PANTHER route. Reason: Correct in substance and one level too shallow. GO:0035725 states both the ion and the fact that transport is across a membrane, which is what a NaV alpha subunit does and what the naked-mole-rat electrophysiology measures. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: sodium ion transmembrane transport Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt Mediates the voltage-dependent sodium ion permeability of PMID:22174253 Acid inhibition of voltage-gated sodium currents is more profound in naked mole-rat nociceptors than in mouse nociceptors, however, which effectively prevents acid-induced action potential initiation. |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: The generic membrane term, mapped from the transmembrane ion-transport domain. The specific compartment, plasma membrane, is independently annotated and is required by the published mechanism. Reason: A strict ancestor of GO:0005886, which is already on this gene product. UniProt states the cell membrane explicitly, so there is no reason to leave the annotation at the uninformative parent. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: plasma membrane Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt SUBCELLULAR LOCATION: Cell membrane |
| GO:0019228 neuronal action potential | IEA GO_REF:0000118 | ACCEPT | Summary: NaV1.7 is the channel that sets the threshold for action potential initiation in peripheral sensory neurons. In the naked mole-rat this function is intact: the species shows normal nocifensive responses to noxious heat and mechanical stimuli, which requires nociceptors that fire normally, and the acid phenotype is specifically a failure of action potential initiation under acidification. Reason: This is the process term the naked-mole-rat literature actually argues about. The published mechanism is that acid prevents action potential initiation in this species by blocking this channel, which presupposes that the channel drives action potential initiation in the first place. Neither the projection nor the species-specific variant gives any reason to doubt participation in neuronal action potentials; only the pH dependence of that participation differs. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000004433 · PAINT node cited by the TreeGrafter row SUPPORTS TRANSFER The naked mole-rat protein sits inside the NaV1.7 subfamily that inherited this role, and the species-specific literature corroborates it directly. Supporting Evidence: PMID:32206859 Voltage-gated sodium channels are necessary for action potential initiation and propagation PMID:34476892 Normal nocifensive responses were reported for noxious heat and mechanical stimuli. PMID:22174253 Thus, evolutionary pressure has selected for an Na(V)1.7 gene variant that tips the balance from proton-induced excitation to inhibition of action potential initiation to abolish acid nociception. |
| GO:0035725 sodium ion transmembrane transport | IEA GO_REF:0000118 | ACCEPT | Summary: The process a NaV alpha subunit carries out: movement of Na+ across the plasma membrane through the channel pore, down its electrochemical gradient, on depolarization. Reason: Core biological process, at the right level of specificity, and directly supported by the naked-mole-rat electrophysiology, which measures voltage-gated sodium currents in this species' nociceptors and their block by protons. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000004433 · PAINT node cited by the TreeGrafter row SUPPORTS TRANSFER Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt Reaction=Na(+)(in) = Na(+)(out) PMID:22174253 Acid inhibition of voltage-gated sodium currents is more profound in naked mole-rat nociceptors than in mouse nociceptors, however, which effectively prevents acid-induced action potential initiation. |
| GO:0055085 transmembrane transport | IEA GO_REF:0000002 | MODIFY | Summary: The most general transport term available from the ion-transport domain signature. The sodium-specific child is already annotated. Reason: A strict ancestor of GO:0035725. It says only that something crosses a membrane, which for a well-characterized sodium-selective channel is a loss of information. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: sodium ion transmembrane transport Supporting Evidence: file:HETGA/Scn9a/Scn9a-uniprot.txt Reaction=Na(+)(in) = Na(+)(out) |
| GO:0086010 membrane depolarization during action potential | IEA GO_REF:0000118 | ACCEPT | Summary: Sodium influx through this channel is what depolarizes the membrane during the upstroke of the action potential. This is the mechanistic biological process of a NaV alpha subunit and the step that fails in naked mole-rat nociceptors when the channel is blocked by protons. Reason: Correct, specific, and the process on which the entire naked-mole-rat acid phenotype turns: when the variant channel is proton-blocked, the depolarization that would initiate the action potential does not occur, which is why acid silences rather than excites these neurons. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000004433 · PAINT node cited by the TreeGrafter row SUPPORTS TRANSFER Supporting Evidence: PMID:34476892 The gene variant in question renders the NaV1.7 channel more susceptible to inhibition by acid, thus shutting down action potential firing in nociceptor fibres. PMID:32206859 Voltage-gated sodium channels are necessary for action potential initiation and propagation |
| GO:0019233 sensory perception of pain | ISS PMID:17167479 An SCN9A channelopathy causes congenital inability to experi... | NEW | Summary: Missing from GOA. The whole naked-mole-rat literature on this protein is about its role in this species' pain phenotype: NaV1.7 is the nociceptor sodium channel whose species-specific variant abolishes acid nociception while leaving heat and mechanical nociception intact. A gene product whose sequence changes selectively remove one pain modality is, by any reasonable reading, involved in sensory perception of pain. Reason: Proposed as an inferred-from-sequence-similarity annotation rather than an experimental one, because the direct manipulations were done on the cloned channel and on nociceptor recordings rather than on the intact animal's gene. The inference is nonetheless unusually well grounded for this species: the human ortholog is an essential and non-redundant requirement for nociception, the naked mole-rat channel is the same subfamily protein with an intact pore, and the naked mole-rat papers explicitly attribute this species' selective analgesia to mutations in this gene. The ISS is therefore anchored on the source-species experiment (PMID:17167479, loss-of-function SCN9A in humans) with the human ortholog UniProtKB:Q15858 recorded as the with/from entity, rather than on the naked mole-rat channel paper PMID:22174253, which remains cited in supported_by as the evidence that this species' variant selectively removes acid nociception. I have not proposed any more specific child term, because the naked mole-rat's distinguishing feature is the loss of one pain modality rather than a positive role in detecting a stimulus. Supporting Evidence: PMID:22174253 We describe a species-specific variant of the nociceptor sodium channel Na(V)1.7, which is potently blocked by protons and can account for acid insensitivity in this species. PMID:34424517 by accumulating mutations in genes encoding proteins that are only now being exploited as targets for new pain therapies (the nerve growth factor receptor TrkA and voltage-gated sodium channel, NaV1.7), this species mastered the art of analgesia before humans evolved PMID:17167479 Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. |
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Download this section (compressed HTML)Q: Should GO create a molecular function term for a channel whose conduction is inhibited by extracellular protons, given that GO:1905151 was obsoleted in 2025 on the grounds that the concept belongs in the molecular function branch, but no molecular function term was created in its place?
Q: Is enhanced proton block of NaV1.7 better captured as a molecular function of the channel, or as a gene-product-independent modulation that GO should not attempt to represent at all? The blocking species is a proton, not a gene product, which is what makes the existing regulator-centred and inhibitor-centred terms unusable.
Q: G9DCX3 is a fragment missing 22 N-terminal and 87 C-terminal residues relative to human NaV1.7. Is this the accession GO should annotate for naked mole-rat Scn9a, or should annotations move to a genome-derived full-length model once one is available? The fragment is the sequence tied to the primary literature, which is a real argument for keeping it.
Q: Does the domain III variant set reported as unique to acid-insensitive African mole-rats contribute to proton block, and if so should the two regions be described as one functional site?
Experiment: Reciprocal mutagenesis in the naked mole-rat channel itself: convert the domain IV EKE triplet at G9DCX3 positions 1698-1700 back to the mammalian KKV and measure proton block and pH-dependent shifts in activation and inactivation in a heterologous expression system. The published work reported the converse experiment, moving naked mole-rat residues into the human protein, so testing the loss-of-adaptation direction would close the loop.
Hypothesis: The acidic EKE triplet in the domain IV S5-pore linker is necessary, and not merely sufficient, for the enhanced proton block of naked mole-rat NaV1.7.
Experiment: Structural or accessibility mapping of the protonation site: cryo-EM of the naked mole-rat channel, or cysteine-accessibility scanning of the domain IV S5-pore linker, at low and neutral extracellular pH, comparing the naked mole-rat and mouse channels.
Hypothesis: The triplet acts through local electrostatics at the outer pore rather than through the voltage sensors.
Experiment: Measure proton block of naked mole-rat NaV1.7 with the domain III variants reverted to the mammalian consensus while the domain IV EKE triplet is left intact, and in the double-reverted channel, to test additivity.
Hypothesis: The domain III variants unique to acid-insensitive African mole-rats add to the proton block conferred by the domain IV triplet.
Experiment: Immunolocalisation of NaV1.7 in naked mole-rat dorsal root ganglia and skin, asking whether the channel occupies axons, intraepidermal terminals and nodes of Ranvier. This is the missing evidence that currently limits the cellular component annotation to plasma membrane.
Hypothesis: Naked mole-rat NaV1.7 occupies the same neuronal subcompartments as its human and mouse orthologs.
Experiment: Sequence and functionally test the domain IV triplet across a broader panel of hystricomorph rodents, including species that are not subterranean, and correlate the triplet with measured burrow CO2 where available. The guinea pig HKV state observed in this review suggests the region is variable within this clade.
Hypothesis: The EKE state tracks burrow hypercapnia rather than hystricomorph phylogeny.
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